Glutamate agents in the treatment of mental disorders

ABSTRACT

Methods of treating mental disorders, including anxiety disorders such as obsessive-compulsive disorder, are provided. The methods comprise administering an effective amount of a glutamate modulator to an individual in need thereof. Also provided are methods of enhancing the activity of a serotonin reuptake inhibitor (SRI) comprising co-administering a glutamate modulator and a serotonin reuptake inhibitor. Pharmaceutical composition comprising a serotonin reuptake inhibitor and a glutamate modulator are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/668,735, filed Apr. 5, 2005; U.S. Provisional Application No.60/669,774, filed Apr. 7, 2005; U.S. Provisional Application No.60/690,187, filed Jun. 13, 2005; U.S. Provisional Application No.60/694,621, filed Jun. 27, 2005; and U.S. Provisional Application No.60/756,472, filed Jan. 4, 2006; the teachings and specifications ofwhich are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Anxiety disorders are often debilitating chronic conditions, which canbe present from an early age or begin suddenly after a triggering event.They are prone to flare up at times of high stress. Anxiety disordersinclude panic disorder, agoraphobia, social anxiety disorder (also knownas social phobia), specific phobia, or simple phobia, generalizedanxiety disorder, obsessive-compulsive disorder, and post-traumaticstress disorder.

Many of these disorders can be treated with the aid of counseling andbehavioral therapies, such as cognitive therapy. Such treatments may beused with or without adjunctive pharmaceutical therapy. A number ofdrugs have been used to treat these disorders, including benzodiazepinesand antidepressants of all main classes: selective serotonin reuptakeinhibitors (“SSRIs”), tricyclic antidepressants (“TCAs”), and monoamineoxidase inhibitors (“MAOIs”).

Obsessive Compulsive Disorder (“OCD”) is an example of an anxietydisorder. It is a debilitating psychiatric condition with a lifetimeprevalence of 2-3%. It is characterized by recurrent, intrusive thoughts(obsessions) and/or repetitive, stereotyped behaviors (compulsions) thatlast for at least one hour per day and significantly interfere with anindividual's normal level of functioning. Although cognitive behavioraltherapy and pharmacotherapy with serotonin reuptake inhibitors (SRI) areeffective treatments for many patients, a subset experience minimalrelief from their symptoms with these standard treatments. When severe,OCD is completely incapacitating with devastating consequences forpatients and their families. Augmentation strategies with neurolepticmedications can improve the effectiveness of SRI therapy but do noteliminate OCD symptoms (Saxena et al., J. Clin. Psychiatry, 57:303-6,1996; McDougle et al., J. Clin. Psychiatry, 56:526-8, 1995) and areassociated with adverse effects when used chronically. Consequently,improved pharmacological treatments are needed. The clinical observationthat few patients experience a complete response to SRI's or dopamineantagonists suggests that other neurochemical systems are involved inthe pathophysiology of OCD.

Thus, there is a need for pharmaceutical therapies that can be used totreat patients with the above disorders, including patients who do notrespond to currently available therapies, as well as for pharmaceuticaltherapies that improve the efficacy of currently available treatmentregimens.

SUMMARY OF THE INVENTION

The present invention solves these and other problems by providingmethods of treating a mental disorder in an individual. In some aspects,the methods comprise administering to the individual an effective amountof a glutamate modulator. In certain embodiments, the disorder is ananxiety disorder, including obsessive-compulsive disorder. In someembodiments, the individual displays a particular score on the YaleBrown Obsessive Compulsive Scale or displays specific symptoms. Incertain embodiments, the glutamate modulator attenuates presynapticglutamate release or normalizes, enhances, or potentiates the uptake ofglutamate by glia. In certain embodiments, the glutamate modulator isriluzole, N-acetylcysteine, a β-lactam, amantadine, lamictal,acamprosate, memantine, neramexane, remacemide, ifenprodil, ordextromethorphan. In certain specific embodiments, the β-lactam is aβ-lactam antibiotic, such as penicillin, amoxicillin, ceftriaxone,cephapirin, cefoperazole, cefadroxil, bacampicillin, ampicillin,cephalothin, or nafcillin.

In another aspect, the invention provides methods of treating a mentaldisorder in an individual in need thereof. The methods compriseadministering to the individual an effective amount of an agent thatnormalizes, enhances, or potentiates glutamate uptake by glia. Incertain embodiments, the disorder is a specific mental disorder. Incertain embodiments, the agent increases the expression, activity, orfunction of at least one glutamate transporter in glia. In specificembodiments, the agent is a glutamate modulating agent, including aβ-lactam. In certain embodiments, the agent protects glial cells againstglutamate toxicity, repletes levels of glutathione, or attenuates toxiclevels of glutamate. In specific embodiments, the agent isN-acetylcysteine.

In yet another aspect, the invention provides methods of enhancing theactivity of a serotonin reuptake inhibitor (SRI) in an individual inneed thereof. The methods comprise co-administering to the individual aglutamate modulator and a SRI, wherein the glutamate modulator isadministered in an amount sufficient to normalize synaptic glutamatelevels in the individual, thereby resulting in greater activity of theSRI in the individual than would occur in the absence ofco-administration of the glutamate modulator. In certain embodiments,the individual has an anxiety disorder, including obsessive-compulsivedisorder. In certain embodiments, the glutamate modulator is riluzole,N-acetylcysteine, a β-lactam, amantadine, lamictal, acamprosate,memantine, neramexane, remacemide, ifenprodil, or dextromethorphan. Incertain embodiments, the glutamate modulator is not riluzole. In certainembodiments, the serotonin reuptake inhibitor is citalopram,escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline,trazodone, venlafaxine, mirtazepine, clomipramine, or combinations withother psychotropic medications including an anti-psychotic, ananti-convulsant, a tricyclic antidepressant, a monoamine oxidaseinhibitor, a selective serotonin reuptake inhibitor, a selectiveserotonin-norepinephrine reuptake inhibitor, a norepinephrine dopaminereuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, abenzodiazepine, a wakefulness promoting agent, anti-manic agent, or acombination of one or more of the foregoing.

The invention also encompasses pharmaceutical compositions comprising aserotonin reuptake inhibitor and a glutamate modulator. In someembodiments, the serotonin reuptake inhibitor is citalopram,escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline,trazodone, venlafaxine, mirtazepine, clomipramine, or combinations withother psychotropic medications including an anti-psychotic, ananti-convulsant, a tricyclic antidepressant, a monoamine oxidaseinhibitor, a selective serotonin reuptake inhibitor, a selectiveserotonin-norepinephrine reuptake inhibitor, a norepinephrine dopaminereuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, abenzodiazepine, a wakefulness promoting agent, anti-manic agent, or acombination of one or more of the foregoing. In some embodiments, theglutamate modulator is riluzole, N-acetylcysteine, a β-lactam,amantadine, lamictal, acamprosate, memantine, neramexane, remacemide,ifenprodil, or dextromethorphan. In some embodiments, the pharmaceuticalcomposition additionally comprises a pharmaceutically acceptablecarrier.

The details of various aspects of the invention are set forth in theaccompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean Y-BOCS score in patients with serotonin reuptakeinhibitor-resistant obsessive-compulsive disorder treated with riluzoleaddition.

FIG. 2 shows pre- and post-treatment HAM-D scores in patients withserotonin reuptake inhibitor-resistant obsessive-compulsive disordertreated with riluzole addition.

FIG. 3 shows HAM-D scores in treatment-resistant depression patientstreated with riluzole addition. FIG. 4 shows compares HAM-D scores forresponders (diamond symbols) and non-responders (square symbols) intreatment-resistant depression patients treated with riluzole addition.

FIG. 5 shows pre- and post-treatment HAM-A scores for anxiety and moodsymptoms patients treated with riluzole.

FIG. 6 shows mean pre- and post-treatment HAM-A scores for anxiety andmood symptoms patients treated with riluzole.

FIG. 7 shows pre- and post-riluzole treatment Massachusetts GeneralHospital (MGH) Hairpulling Scale and Psychiatric InstituteTrichotillomania Scale (PITS) score for a patient treated with riluzole.

FIG. 8 shows pre- and post-riluzole treatment Massachusetts GeneralHospital (MGH) Hairpulling Scale score for a patient treated withriluzole.

FIG. 9 shows the effects of riluzole in a patient diagnosed withtrichotillomania.

FIG. 10A shows YBOCS, HAM-D, and HAM-A scores for a patient over thefirst month of treatment with riluzole.

FIG. 10B shows Skin Picking Impact Scale (SPIS) scores for a patientover the first six weeks of treatment with riluzole, scoredretrospectively by the patient's self-report.

FIG. 11 shows the dose of NAC, Y-BOCS scores, and HAM-D scores in apatient with SRI-resistant OCD treated with fluvoxamine 300 mg and NAC 3g (total daily doses).

FIG. 12 shows the results of a tail suspension test in mice treated withceftriaxone.

DETAILED DESCRIPTION Mental Disorders

The methods and compositions of the instant invention are useful in thetreatment of various mental disorders. Such disorders are defined andcategorized in the Diagnostic and Statistical Manual of MentalDisorders, 4^(th) Ed., Text Revision (“DSM-IV-TR”), American PsychiatricAssociation, Washington, D.C., 2000. The term “mental disorder”, as usedherein, is not intended to imply a distinction between “physical” and“mental” disorders and is considered to encompass the full breadth ofdisorders described in DSM-IV-TR. Examples of classes of mentaldisorders usefully treated by to the methods and compositions of theinstant invention include, e.g., disorders usually first diagnosed ininfancy, childhood, or adolescence; delirium, dementia, or amnestic orother cognitive disorders; mental disorders due to a general medicalcondition; substance-related disorders; schizophrenia or other psychoticdisorders; mood disorders; anxiety disorders; somatoform disorders;factitious disorders; dissociative disorders; sexual or gender identitydisorders; eating disorders; sleep disorders; impulse-control disorders;and adjustment disorders. In certain embodiments, the methods andcompositions of the invention are used to treat mood disorders andanxiety disorders. In some embodiments, the mood disorder is majordepression disorder. In some embodiments, the anxiety disorder isobsessive-compulsive disorder. Other disorders that can be treated usingthe methods and compositions of the instant invention include bipolardisorder, schizophrenia, tic disorders, Tourette's disorder, generalizedanxiety disorder, and other neuropsychiatric disorders. In someembodiments of the invention, the individual does not have majordepressive disorder. In some embodiments, the individual has more thanone disorder.

In some embodiments of the invention, the individual treated accordingto the claimed method is assessed using the Yale Brown ObsessiveCompulsive Scale (“Y-BOCS”). See Goodman et al., Arch. Gen. Psychiatry46:1006-1011, 1989. According to this system, an individual is scoredusing a symptom checklist by asking the individual about specificobsessions and compulsions. Such symptoms are broadly categorized asaggressive obsessions, contamination obsessions, sexual obsessions,hoarding/saving obsessions, religious obsessions, obsession with needfor symmetry or exactness, miscellaneous obsessions, somatic obsessions,cleaning/washing compulsions, checking compulsions, repeating rituals,counting compulsions, ordering/arranging compulsions, and miscellaneouscompulsions. Each of these categories is further divided by subcategoryof more specific symptoms. Individuals are scored according to theanswers provided. Scores range from 0-7 for subclinical, 8-15 for mild,16-23 for moderate, 24-31 for severe, and 32-40 for extreme severity. Insome embodiments of the invention, the individual displays a Yale BrownObsessive Compulsive Scale score of at least 20 prior to treatment. Inother embodiments, the individual displays a score of at least 24, atleast 28, at least 32, or at least 36 prior to treatment.

According to the Y-BOCS system, the broad symptom categories may befurther subdivided. Subcategories of aggressive obsessions include: fearmight harm self; fear might harm others; violent or horrific images;fear of blurting out obscenities or insults; fear of doing somethingelse embarrassing; fear will act on unwanted impulses (e.g., to stabfriend); fear will steal things; fear will harm others because notcareful enough; (e.g. hit/run motor vehicle accident); and fear will beresponsible for something else terrible happening (e.g., fire,burglary). Subcategories of contamination obsessions include: concernsor disgust w\ with bodily waste or secretions (e.g., urine, feces,saliva), concern with dirt or germs; excessive concern withenvironmental contaminants (e.g. asbestos, radiation toxic waste);excessive concern with household items (e.g., cleansers solvents);excessive concern with animals (e.g., insects); bothered by stickysubstances or residues; concerned will get ill because of contaminant;concerned will get others ill by spreading contaminant (aggressive); andno concern with consequences of contamination other than how it mightfeel. Subcategories of sexual obsessions include: forbidden or perversesexual thoughts, images, or impulses; content involves children orincest; content involves homosexuality; and sexual behavior towardsothers (aggressive). Subcategories of religious obsessions include:concerned with sacrilege and blasphemy; and excess concern withright/wrong, morality. Subcategories of obsession with need for symmetryof exactness include: accompanied by magical thinking (e.g., concernedthat another will have accident dent unless things are in the rightplace); and not accompanied by magical thinking. Subcategories ofmiscellaneous obsessions include: need to know or remember; fear ofsaying certain things; fear of not saying just the right thing; fear oflosing things; intrusive (nonviolent) images; intrusive nonsense sounds,words, or music; bothered by certain sounds/noises; lucky/unluckynumbers; colors with special significance; and 3 superstitious fears.

Subcategories of somatic obsessions include: concern with illness ordisease; and excessive concern with body part or aspect of appearance(eg., dysmorphophobia). Subcategories of cleaning/washing compulsionsinclude: excessive or ritualized handwashing; excessive or ritualizedshowering, bathing, toothbrushing grooming, or toilet routine, involvescleaning of household items or other inanimate objects; and othermeasures to prevent or remove contact with contaminants. Subcategoriesof checking compulsions include: checking locks, stove, appliances etc.;checking that did rot/will not harm others; checking that did not/willnot harm self; checking that nothing terrible did/will happen; checkingthat did not make mistake; and checking tied to somatic obsessions.Subcategories of repeating rituals include: rereading or rewriting; andneed to repeat routine activities (jog, in/out door, up/down fromchair). Subcategories of miscellaneous compulsions include: mentalrituals (other than checking/counting); excessive listmaking; need totell, ask, or confess; need to touch, tap, or rub; rituals involvingblinking or staring; measures (not checking) to prevent: harm toself-harm to others terrible consequences; ritualized eating behaviors;superstitious behaviors; Trichotillomania; other self-damaging orself-mutilating behaviors.

Glutamate Modulators

The glutamate modulators of the instant invention are agents thatnormalize glutamate levels in an individual to whom they areadministered. Glutamate modulators of utility in the invention include,for example, agents that attenuate or normalize presynaptic glutamaterelease or that normalize, enhance, or potentiate the uptake ofglutamate by glia. The term is also intended to encompass any agent thatattenuates or normalizes the intracellular modulators of the response toglutamate (e.g., protein kinase C (“PKC”) inhibitors, calcium channelblockers, inhibitors of voltage gated sodium channels, inhibitors ofvoltage gated calcium channels, and N P Q voltage gated calciumchannels). The term is also intended to encompass agents that areantagonists at AMPA receptors, agents that modulate IP3 or ryanodinereceptors, agents that act as mGlu Group I receptor antagonists, agentsthat act as mGlu receptor Group II and III agonists, and agents that acton the cysteine-glutamate antiporter.

In some embodiments, the glutamate modulator is an agent that increasesexcitatory amino acid transporter function. In specific embodiments, theglutamate modulator is an agent that enhances function or expression ofexcitatory amino acid transporters (EAAT) located on glia and neurons.

In some embodiments of the invention, the glutamate modulator isriluzole, N-acetylcysteine, a β-lactam, amantadine, lamictal,acamprosate, memantine, neramexane, remacemide, ifenprodil, ordextromethorphan.

In more specific embodiments of the invention, the glutamate modulatoris riluzole.

In other embodiments, the glutamate modulator is N-acetylcysteine, aβ-lactam, amantadine, lamictal, acamprosate, memantine, neramexane,remacemide, ifenprodil, or dextromethorphan. The β-lactam may be aβ-lactam antibiotic, such as, for example, penicillin, amoxicillin,ceftriaxone, cephapirin, cefoperazole, cefadroxil, bacampicillin,ampicillin, cephalothin, or nafcillin. In specific embodiments, theglutamate modulator is ceftriaxone.

The β-lactams of the invention include those β-lactam compounds that areknown in the art. See, e.g., U.S. Pat. Nos. 5,310,897 and 6,031,094.These and other β-lactams of the invention may be synthesized bystandard chemical techniques as is well known in the art. In some cases,the β-lactams are β-lactam antibiotics.

In some embodiments of the invention, the glutamate modulator includesmore than one of the above-defined glutamate modulators.

The glutamate modulators of the instant invention may contain one ormore asymmetric elements such as stereogenic centers or stereogenic axese.g. asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. For compounds with two or moreasymmetric elements, these compounds can additionally be mixtures ofdiastereomers. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms; all isomeric forms of the compounds areincluded in the present invention. In these situations, the singleenantiomers (optically active forms) can be obtained by asymmetricsynthesis, synthesis from optically pure precursors, or by resolution ofthe racemates. Resolution of the racemates can also be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column.

Unless otherwise specified, or clearly indicated by the text, aglutamate modulator of the instant invention includes the free base orfree acid forms of the modulator, if any, as well as any and allpharmaceutically acceptable salt forms of the modulator. Such salt formsinclude derivatives of the modulator, wherein the parent compound ismodified by making non-toxic acid or base addition salts thereof, andalso include pharmaceutically acceptable solvates, including hydrates,of such compounds and such salts. Examples of pharmaceuticallyacceptable salt forms include, but are not limited to, mineral ororganic acid addition salts of basic residues such as amines; alkali ororganic addition salts of acidic residues such as carboxylic acids; andthe like, and combinations comprising one or more of the foregoingsalts. The pharmaceutically acceptable salts include non-toxic salts andthe quaternary ammonium salts of the parent compound formed, forexample, from non-toxic inorganic or organic acids. For example,non-toxic acid salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric;other acceptable inorganic salts include metal salts such as sodiumsalt, potassium salt, and cesium salt; and alkaline earth metal salts,such as calcium salt and magnesium salt; and combinations comprising oneor more of the foregoing salts.

Pharmaceutically acceptable organic salts include salts prepared fromorganic acids such as acetic, trifluoroacetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4; organic amine salts such astriethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt; and amino acid salts such asarginate, asparginate, and glutamate, and combinations comprising one ormore of the foregoing salts.

The compounds of the invention may be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

As used herein, the compounds of the invention are defined to includepharmaceutically acceptable derivatives or prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of this invention, which, upon administrationto a recipient, is capable of providing or provides (directly orindirectly) a compound of this invention.

Accordingly, this invention also provides prodrugs of the compounds ofthe invention, which are derivatives that are designed to enhancebiological properties such as oral absorption, clearance, metabolism orcompartmental distribution. Such derivations are well known in the art.

As the skilled practitioner realizes, the compounds of the invention maybe modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological compartment (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The term “protected” refers to the attachment of a suitable chemicalgroup (protecting group) to the designated functional group. Examples ofsuitable amino protecting groups and protecting groups are described inGreene and Wuts, Protective Groups in Organic Synthesis, 2d. Ed., JohnWiley and Sons, 1991; Fieser and Fieser, Fieser and Fieser's Reagentsfor Organic Synthesis, John Wiley and Sons, 1994; Paquette, ed.Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,1995.

Certain derivatives and prodrugs are those that increase thebioavailability of the compounds of the invention when such compoundsare administered to an individual (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood), havemore favorable clearance rates or metabolic profiles, or enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species. Examples ofprodrugs include derivatives in which a group that enhances aqueoussolubility or active transport through the gut membrane is appended tothe structure.

Serotonin Reuptake Inhibitors

The methods and compositions of the invention relate to the use ofglutamate modulators to enhance the activity of a serotonin reuptakeinhibitor (“SRI”). SRIs, including selective SRIs (“SSRIs”) are wellknown in the art and are widely used in the treatment of mood disorders,as well as in the treatment of other mental disorders. In one aspect ofthe invention, the activity of an SRI is enhanced in an individual inneed thereof. The method comprises co-administering to the individual aglutamate modulator and a SRI, wherein the glutamate modulator isadministered in an amount sufficient to normalize synaptic glutamatelevels in the individual, thereby resulting in greater activity of theSRI in the individual than would occur in the absence ofco-administration of the glutamate modulator. In a specific embodimentof the invention, the SRI is citalopram, escitalopram, flouxetine,fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine,mirtazepine, clomipramine, or combinations with other psychotropicmedications including an anti-psychotic, an anti-convulsant, a tricyclicantidepressant, a monoamine oxidase inhibitor, a selective serotoninreuptake inhibitor, a selective serotonin-norepinephrine reuptakeinhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promotingagent, anti-manic agent, or a combination of one or more of theforegoing.

Administration and Dosage

The methods and compositions of the instant invention are used to treatindividuals of any mammalian species, including domestic livestock, suchas horses, cattle, sheep, pigs, goats, bison, model experimentalanimals, such as mice, rats, guinea pigs, and rabbits, domestic petssuch as dogs and cats, and human beings. The methods and compositionsare preferably used to treat human beings.

The term “treating” as used herein refers to the lessening oralleviation of symptoms of a particular disorder in an individual or theimprovement of an ascertainable measurement associated with a particulardisorder.

In one aspect, the invention provides pharmaceutical compositionscomprising a serotonin reuptake inhibitor and a glutamate modulator. Analternate embodiment provides compositions comprising a serotoninreuptake inhibitor, a glutamate modulator, and a pharmaceuticallyacceptable carrier.

The term “pharmaceutically acceptable carrier” refers to a carrier thatmay be administered to a patient, together with a compound of thisinvention, and which does not destroy the pharmacological activity ofthe compound and is nontoxic when administered in doses sufficient todeliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers that may be used in thepharmaceutical compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin,self-emulsifying drug delivery systems (SEDDS) such as α-tocopherol,polyethyleneglycol 1000 succinate, surfactants used in pharmaceuticaldosage forms such as Tweens or other similar polymeric deliverymatrices, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, andγ-cyclodextrin, or chemically modified derivatives such ashydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be advantageously used to enhance delivery of the compounds of theinvention.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal,intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as those described in Pharmacopeia Helvetica (Ph.Helv.) or a similar alcohol, or carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms such as emulsions and/orsuspensions. Other commonly used surfactants such as Tweens or Spansand/or other similar emulsifying agents or bioavailability enhancerswhich are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

The pharmaceutical compositions of the present invention mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of activeingredient that can be combined with a carrier material to produce asingle dosage form will vary depending upon the host being treated, theparticular mode of administration. The amount of active ingredient thatcan be combined with a carrier material to produce a single dosage formwill generally be that amount of the compound that produces atherapeutic effect. Generally, out of one hundred percent, this amountwill range in some embodiments from about 1 percent to about ninety-ninepercent of active ingredient, in some embodiments from about 5 percentto about 70 percent, and in some embodiments from about 10 percent toabout 30 percent.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, gender, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In some embodiments, the active compound will be administeredonce daily.

In another aspect of the invention, the compounds of the invention areadministered alone or co-administered with another therapeutic agent. Asused herein, the phrase “co-administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe desired effect is obtained. For example, the second compound isadministered while the previously administered therapeutic compound isstill effective in the body (e.g., the two compounds are simultaneouslyeffective in the patient, which may include synergistic effects of thetwo compounds). The different therapeutic compounds may be administeredeither in the same formulation or in a separate formulation, eitherconcomitantly or sequentially. Thus, an individual who receives suchtreatment may benefit from a combined effect of different therapeuticcompounds. Co-administration includes simultaneous or sequentialadministration of two or more compounds.

In certain embodiments, a glutamate modulator of the present inventionis co-administered with a serotonin reuptake inhibitor. The serotoninreuptake inhibitor is, for example, citalopram, escitalopram,flouxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine,mirtazepine, clomipramine, or combinations with other psychotropicmedications including an anti-psychotic, an anti-convulsant, a tricyclicantidepressant, a monoamine oxidase inhibitor, a selective serotoninreuptake inhibitor, a selective serotonin-norepinephrine reuptakeinhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promotingagent, anti-manic agent, or a combination of one or more of theforegoing.

Effects of Glutamate Modulators

The glutamate modulators of the instant invention may usefully attenuatepresynaptic glutamate release or normalize, enhance, or potentiate theuptake of glutamate by glia. Without intending to be bound by theory, itis believed that agents that reduce glutamate hyperactivity, or itsconsequences, in the central nervous system might be efficacious astherapeutic interventions. See, e.g., Pittenger et al., The Journal ofthe American Society for Experimental NeuroTherapeutics 3:69-81, 2006.Such agents are especially useful in the treatment of individuals withobsessive-compulsive disorder and, in particular, those individuals thatare resistant to treatment with other agents, such as serotonin reuptakeinhibitors. Coric et al., Psychopharmacology. 167:210-220, 2003. Coricet al., Biological Psychiatry. 58:424-428, 2005.

In some embodiments of the invention, the glutamate modulators of theinvention attenuate presynaptic glutamate release. For example, riluzoleis FDA-approved as a neuroprotectant in the treatment of amyotrophiclateral sclerosis (“ALS”). The pharmacology of riluzole includes: 1) aninhibitory effect on glutamate release, 2) inactivation ofvoltage-dependent sodium channels, and 3) ability to interfere withintracellular events that follow transmitter binding at excitatory aminoacid receptors. See Physician's Desk Reference, 59^(th) Ed, 744-746,2005, Thomson, Montvale, N.J. In some embodiments of the invention, theglutamate modulators of the invention normalize, enhance, or potentiatethe uptake of glutamate by glia. For example, N-acetylcysteine is widelyused for its antioxidant properties and as an antidote for acetaminophentoxicity. See U.S. Pat. No. 6,566,401. It also modulates CNS glutamate(Pittenger et al., The Journal of the American Society for ExperimentalNeuroTherapeutics 3:69-81, 2006) and is effective in treatingSRI-refractory obsessive-compulsive disorder (see below). Withoutintending to be bound by theory, N-acetylcysteine may cause glialrelease of glutamate into the extrasynaptic space, where it maystimulate inhibitory metabotropic glutamate receptors on glutamatergicnerve terminals and thus reduce the synaptic release of glutamate.Pittenger et al., The Journal of the American Society for ExperimentalNeuro Therapeutics 3:69-81, 2006. N-acetylcysteine may also protectglial cells against glutamate toxicity, replete levels of glutathione,and attenuate toxic levels of glutamate. Id. In some embodiments of theinvention, the glutamate modulators of the invention increase theexpression, activity, or function of at least one glutamate transporterin glia. For example, β-lactam antibiotics upregulate the glialglutamate uptake transporter and display neuroprotective effects in amouse model of ALS. Rothstein et al., Nature, 433:73-77, 2005.

It will be readily apparent to one of ordinary skill in the relevantarts that other suitable modifications and adaptations to the methodsand applications described herein may be made without departing from thescope of the invention or any embodiment thereof. Having now describedthe present invention in detail, the same will be more clearlyunderstood by reference to the following Example, which is includedherewith for purposes of illustration only and is not intended to belimiting of the invention.

EXAMPLE 1 Riluzole Augmentation in Treatment-ResistantObsessive-Compulsive Disorder Methods and Materials

Thirteen patients were recruited from the Yale OCD Research Clinic.Patient characteristics and inpatient/outpatient status are listed inTable 1. All patients provided written informed consent prior to studyparticipation. The study was approved by the Yale University HumanInvestigations Committee, New Haven, Conn. Patients between the ages 18and 65 with a primary DSM-IV diagnosis of OCD who had failed toclinically respond to at least eight weeks of treatment with SRIs wereeligible for study participation. Treatment failure was defined by aYale-Brown Obsessive Compulsive Scale (Y-BOCS) score >16 despite atleast eight weeks of treatment with the maximum tolerated dose of an SRImedication. Additionally, OCD symptoms had to be present for at leastone year and at least of moderate severity on the Clinical GlobalImpression Scale severity of illness item. Patients with a primarypsychotic disorder, prior psychosurgery for OCD, illicit substance useover the past one month, seizure disorder, significant head trauma,acute medical illnesses, or elevated baseline LFT's (i.e., greater thantwice the upper limits of normal) were excluded from studyparticipation. Diagnoses were confirmed using the Structured ClinicalInterview for Axis I DSM-IV Disorders. Major depression was the mostcommon comorbid diagnosis, occurring in 10 of the 13 patients. Patientshad to have failed at least eight weeks of treatment on their currentSRI medication. Concomitant psychotropic medications were permitted onlyif prescribed at a stable dose for at least one month prior to beginningthe trial.

Study duration was initially six weeks. After results from initialsubjects suggested ongoing therapeutic response with time, the study wasextended to nine weeks and then to twelve weeks.

Riluzole was initiated and maintained at a dose of 50 mg twice a day.Subjects were evaluated weekly with clinician-administered ratingscales: Y-BOCS, Clinical Global Impression/Global Improvement item(CGI/GI), Hamilton Depression Inventory (HAM-D), and Hamilton AnxietyInventory (HAM-A). Liver function tests were monitored at baseline andevery three weeks throughout the study. Because of the variable time oftreatment (6-12 weeks), Y-BOCS, HAM-D and HAM-A were analyzed in SASPROC MIXED using mixed effects models with time (baseline to week 9) asfixed effect and a structured variance-covariance pattern matrix(Gueorguieva and Krystal, Archives of General Psychiatry 61: 310-317,2004; Brown and Prescott, Applied Mixed Models in Medicine, John Wiley &Sons 1999; New York, N.Y.). CGI/GI was analyzed using the same modelwith time (baseline to week 7) as fixed effect. The best fittingvariance-covariance matrix according to the Akaike Information Criterionwas selected.

Results

Thirteen patients entered the study and only one subject, a treatmentresponder, dropped out at week nine due to a family situation. PreviousSRI treatment trials, history of augmentation strategies, previouscognitive behavioral therapy, dosage of concomitant medications, andoutcome variables for each patient are shown in Table 2. The mean numberof previously failed medication trials included 3.5 (±1.7) SRI/SNRI/TCAtrials and 1.3 (±1.5) dopamine antagonist augmentation trials.Additionally, twelve of thirteen subjects failed previous trials ofcognitive behavioral therapy. Mean doses of concomitant medicationsduring the study, dosed alone or in combination, included: fluoxetine 80mg (n=4), clomipramine 262.5 mg (n=4), escitalopram 20 mg (n=2),fluvoxamine 300 mg (n=3), buspirone 30 mg (n=1), risperidone 5 mg (n=1),olanzapine 11.3 mg (n=2), quetiapine 50 mg (n=1), and clonazepam 1.3 mg(n=5). Mean Y-BOCS score of patients entering the study was 30.7 (±6.6),indicating severe OCD symptoms. Data from one patient was previouslypublished as a case report (Coric et al. 2003).

FIG. 1 illustrates the mean Y-BOCS score for all study participants.Mean Y-BOCS for the group at baseline was 30.7 (±6.6) and at end ofstudy was 17.7 (±8.6), representing an overall 42% reduction for theentire cohort. Y-BOCS scores improved significantly over time(F_(1,11.1)=19.78, p=0.001). Seven of thirteen patients (54%)demonstrated a >35% reduction in Y-BOCS scores. Five of thirteenpatients (39%) were categorized as treatment responders, as defined by a35% or greater reduction in baseline Y-BOCS, a final Y-BOCS of 16 orless, and consensus of the treating clinicians. Percent reduction inbaseline Y-BOCS scores at end of study ranged from 38-76% in responders.Two out of the five responders were characterized predominantly byhoarding behaviors. Clinician administered CGI/GI scores significantlyimproved over time (F_(1,16.2)=20.99,p=0.0003). Mean baseline CGI/GI was4 (±0), week 6 CGI/GI was 3.2 (±0.6), week 9 CGI/GI was 2.66 (±0.5), andweek 12 CGI/GI was 2.33 (±1).

Mean HAM-D at baseline was 30 (±13.7) and at end of study was19.7(±6.0). FIG. 2. HAM-D scores for the entire group improvedsignificantly over time (F_(1,10.8)=9.12, p=0.012); six out of thirteenpatients demonstrated clinically significant improvements in HAM-Dscores with 36-83% reductions in baseline HAM-D scores by the end of thestudy. Mean HAM-A at baseline was 18.2 (±6.2) and at end of study was 12(±2.5). HAM-A scores improved significantly over time (F_(1,11.2)=7.9,p=0.017). Riluzole was well tolerated and no serious adverse events werenoted. Asymptomatic, transient increases in at least one LFT were notedin four of thirteen patients. One patient experienced a nine-foldincrease in ALT; repeat ALT in that patient revealed a four-foldincrease that normalized to within two times the upper limits of normalby week three. Mean baseline AST, ALT, and Alk Phos were 19.1 (±5.7),22.9 (±12.3), 75 (±13.5), respectively; Mean week six AST, ALT, and AlkPhos were 22 (±13.84), 35.3 (±28.3), 83.7 (±24.4).

A control group of patients with treatment-resistant depression alonealso showed significant improvement of HAM-D scores in response toriluzole in this study. See FIGS. 3 and 4.

TABLE 1 Clinical Characteristics of Patients with OCD Treated withRiluzole Addition to SRI Patient No./ Age at Type of Age(y)/Sex/ onsetof Duration OCD Comorbid Psychiatric Family Ethnicity OCD (y) of OCD (y)Symptoms Diagnoses History 001/34/M/W^(‡) 11 23 Agg, sex MDD OCD (pgrandfather); anorexia (sister) 002/53/F/W^(‡) 48 5 Agg, sex MDD, TicSuicide (p grandfather, p uncle) 003/29/M/W 10 19 Agg, ctm, rel, MDD,Tic OCD (father) cln/was, chk, cnt, ntk 004/50/F/W 23 27 Sym/ext, MDDNone ord/arr 005/36/M/W^(‡) 22 14 Chk, rpt, ntk None OCD (father); MDD(mother); Panic Disorder (father); GAD (brother, sister) 006/23/F/W^(‡)22 1 Som, ctm, MDD None cln/was 007/61/F/W 30 31 Hrd, sym/ext, None OCD(mother); chk, rpt, cnt, alcohol abuse (father) ord/arr, ntk008/30/M/W^(‡) 16 14 Agg, sex, rel, MDD None chk, cnt 009/61/F/AA 43 18Hrd, rel MDD None 010/29/F/W^(‡) 18 11 Cln/was, cnt, MDD OCD (mgrandfather); sym/ext, chk, schizophenia (p cnt, rpt, hrd grandmother)011/46/F/W^(‡) 24 22 Ctm, hrd, None None cln/was, chk, sym/ext012/30/F/W 22 8 Chk, sym/ext, MDD None rpt, ord/arr, ntr 013/50/M/W^(‡)21 29 Sym/ext, ctm, MDD MDD (father, m cln/was, hrd, grandmother +father, chk, rpt, p aunt + uncle); ord/arr, ntk alcohol abuse (father)OCD, obsessive-compulsive disorder; MDD, major depressive disorder; GAD,generalized anxiety disorder; Panic, Panic Disorder; Tic, Tic Disorder;M, male; F, female; W, Caucasian; AA, African-American; m, maternal; p,paternal Agg indicates aggressive; sym/ext, symmetry/exactness; chk,checking; ntk, need to know; rpt, repeating; ord/arr,ordering/arranging; ctm, contamination; cln/wsh; cleaning/washing; som,somatic; rel, religious; hrd, hoarding; cnt, counting; ntr, need totouch, tap, or rub; and sex, sexual. ^(‡)Treated as inpatient

TABLE 2 Treament Data of Patients with OCD treated with RiluzoleAddition to SRI No. of Previous Pre/ Pre/ Pre/ Previous SRI PreviousPrevious Daily CGI Post Post Post Pt Medication Treatment NeurolepticBehavioral Current SRI Concommittant Treatment YBOCS HAM-D HAM-A No.Trials Trials Augmentat. Therapy SRI Dose Medications Response ScoreScore Score  1^(b) 4 Citalopram, Yes Yes Fluvoxamine 300 mg Clonazepam 319/11*  52/33* 22/20 fluvoxamine, 1 mg qhs venlafaxine  2^(b) 3Sertraline Yes No Clomipramine 350 mg Olanzapine 4 18/14* 37/25 18/157.5 mg qhs  3^(b) 6 Fluvoxamine, Yes Yes Clomipramine 225 mg Buspar 335/34  12/12  7/3* fluoxetine, 30 mg qhs paroxetine, citalopram,sertraline, venlafaxine  4^(a) 7 Sertraline, Yes Yes Escitalopram 20 mgNone 4 40/39  25/29 14/31 fluoxetine, citalopram, paroxetine,escitalopram, clomipramine, fluvoxamine  5^(b) 4 Fluvoxamine, No YesFluoxetine 80 mg Quetiapine 3 32/28  15/13 14/14 clomipramine, 50 mg qhsbuspirone  6^(a) 2 Escitalopram Yes Yes Escitalopram 20 mg Risperidone 237/16*  56/16* 25/8* 5 mg qhs  7^(c) 2 Fluoxetine No Yes Fluoxetine 80mg None 3 31/13* 17/20 13/12  8^(c) 5 Sertraline, Yes Yes Clomipramine250 mg Olanzapine 3 35/32  28/30 22/15 fluvoxamine, 15 mg qhs,paroxetine, Clonazepam clomipramine 0.5 mg tid  9^(c) 3 Fluvoxamine, NoYes Fluoxetine 80 mg None 1 33/8*   41/11*  29/10* fluoxetine 10^(c) 2Fluvoxamine Yes Yes Fluvoxamine 300 mg Clonazepam 3 32/20*  31/20* 19/150.5 mg bid 11^(c) 1 Fluoxetine No Yes Fluoxetine 80 mg Clonazepam 234/20* 18/3* 11/4* 0.5 mg qid 12^(c) 4 Fluoxetine, Yes Yes Clomipramine225 mg Topiramine 2 28/21  25/19  18/11* escitalopram, 50 mg bid,fluvoxamine, Clonazepam paroxetine 1 mg qhs 13^(c) 3 Paroxetine, No YesFluvoxamine 300 mg None 2 25/12*  33/18* 24/9* fluvoxamine, clomipramineAbbreviations: YBOCS, Yale Brown Obsessive Compulsive Scale; Ham-D,Hamilton Depression Rating Scale; Ham-A, Hamilton Anxiety Rating Scale;CGI, Clinical Global Impressions; bid, two times a day; tid, three timesa day; qid, four times a day; qhs, given at bedtime *>35% reduction inpre/post rating scales ^(a)Study duration 6 weeks ^(b)Study duration 9weeks ^(c)Study duration 12 weeks ^(c−)Subject enrolled for 12 weekstudy, responded to treatment, and dropped from study at week 9 due tofamily situation (represents the only study drop-out)

Discussion

This open label study suggests that directly attenuating glutamatergicactivity may be efficacious in treatment-resistant OCD. Furthermore, theobserved improvements in Y-BOCS, HAM-D, and HAM-A scores after additionof riluzole is consistent with recent clinical reports suggesting thatmodulation of glutamatergic pathways using the antiglutamatergic agentriluzole may provide symptom relief in anxiety and mood disorders (Coricet al., Psychopharmacology 167:210-220, 2003; Sanacora et al., Am JPsychiatry. 161 (11):2132, 2004; Zarate et al., Am. J. Psych. 161:171-4,2004).

Effective OCD treatment with SRI medications has been observed to leadto a reduction in glutamatergic tone in the CST network (Rosenberg etal., J. Am. Acad. Child Adolesc. Psychiatry 39 (9):1096-103, 2000).Although OCD has been associated with increased activity in the CSTnetwork, it may not be associated with a global increase inglutamatergic function. In fact, a recent report shows reduced glutamateconcentrations in the anterior cingulate gyrus in both OCD and majordepression (Rosenberg et al., J. Am. Acad. Child Adolesc. Psychiatry 43(9):1146-53, 2004). Further study is required to determine whetherriluzole preferentially targets components of the CST circuitry or has amore global effect. Additionally, the role of glutamate in thepathophysiology of mood and anxiety disorders is yet to be elucidated.The relationship between glutamate or Glx levels measured with ¹H-MRSand the rate of glutamatergic neurotransmission is also far from clear(Seibyl et al., Neurobiology of Mental Illness, Charney et al., eds.,Oxford Univ. Press, NY, 170-189, 2001). Glutamate is present in allbrain cells, where it participates in a number of cellular functionsunrelated to neurotransmission. While glutamate is the substrate forglutamatergic neurotransmission, it is not clear whether increases ordecreases in glutamate levels measured by ¹H-MRS reflect increasedsynaptic glutamate release. The extent to which synaptic orextrasynaptic glutamate contribute to the ¹-MRS glutamate signal isunknown. We hypothesize that riluzole may reduce synaptic glutamate byattenuating elevations in extrasynaptic glutamate levels that may ariseas a consequence of impairment of glial glutamate uptake (Sanacora etal., Ann. N.Y. Acad. Sci. 1003:292-308, 2003). Thus, the antidepressantefficacy of riluzole could be consistent with studies describingelevations (Sanacora et al., Arch. Gen. Psychiatry, 61:705-713, 2004) ordecreases (Auer et al., Biol. Psychiatry 47 (4):305-13, 2000) incortical glutamate levels. Future studies employing ¹³C-MRS that canseparate glial and neuronal metabolic rates will be needed to define thenature of glutamatergic disturbances in OCD and depression (Lebon etal., J. Neurosci. 22 (5):1523-31, 2002; Shen et al., Proc. Natl Acad.Sci. USA. 96 (14):8235-40, 1999).

The most common comorbid psychiatric illness in the current study wasmajor depressive disorder (MDD). Studies suggest that the presence ofMDD in patients with OCD negatively affects treatment outcome (Foa etal., J. Consult. Clin. Psychol. 51:287-297, 1983; Overbeck et al., J.Clin. Psychiatry 63:1106-1112, 2002). With recent estimates of thecomorbidity between OCD and MDD ranging from 21 to 54% (Abramowitz, J.Clin. Psychol. 60:1133-1141, 2004), the higher than expected percentageof study subjects with these comorbid disorders (77%) likely reflectsthe severity of treatment resistance in our study population. It isimportant to note that the efficacy of riluzole augmentation intreatment-resistant OCD remained significant even when covarying for themagnitude of antidepressant effect in the current study. The clinicalobservation that SRIs, dopamine antagonists and now riluzole are usefulfor both mood and OCD symptoms suggests a partial overlap between thepathophysiology of these disorders.

Riluzole was well tolerated in our study and no patients discontinuedtreatment due to adverse effects. Riluzole is generally associated withtransient elevations in LFTs; more than 50% of patients treated withriluzole experience elevations in at least one LFT measure andapproximately 2% experience LFT elevations greater than five times theupper limit of normal (Aventis 2004). According to the Physician's DeskReference,

LFTs should be monitored every month during the first three months oftreatment, every three months during the remainder the first year, andthen periodically. Serum LFTs should be monitored more frequently inpatients who develop elevations. Riluzole therapy was discontinued forLFT elevations >5× normal in ALS field trials. In the current study, onepatient demonstrated an asymptomatic increase in ALT that exceeded ninetimes normal, but ALT quickly declined upon repeat testing and carefulweekly monitoring. LFTs were monitored every third week in the currentstudy and more frequently in those patients who developed significantelevations.

This study has several limitations, including its open-label design,relatively small number of patients, lack of a washout prior toinitiation of riluzole and concomitant treatment with standardpsychotropic medications. Use of concomitant medications makes itimpossible to determine whether treatment response was due to riluzolealone or its combination with other medications. This study also doesnot address the long-term effects of treatment with riluzole. Finally,patients were required to have had stable medications regimens for onlyfour weeks prior to study initiation, raising the possibility that someof the treatment effect represented a delayed response to the earlierinitiation of other medications. Despite these limitations, thesignificant improvement in Y-BOCS scores in this treatment-resistantpopulation suggests that riluzole addition may be of practical clinicalbenefit in patients with OCD. Moreover, riluzole's efficacy in thecurrent study has important theoretical implications for the potentialrole of glutamatergic systems in treatment of anxiety and mooddisorders. Future placebo-controlled studies in larger populations iswarranted to follow-up on these promising preliminary findings.

EXAMPLE 2 Use of Glutamate Modulating Agents for Treatment of AnxietyDisorders and Trichotillomania Anxiety Disorders

A study of thirteen patients with anxiety and mood symptoms wasundertaken. Patients' baseline anxiety was measured using the HamiltonAnxiety Scale (HAM-A). The HAM-A is a rating scale developed to quantifythe severity of anxiety symptomatology, often used in psychotropic drugevaluation. It consists of 14 items, each defined by a series ofsymptoms. Each item is rated on a 5-point scale, ranging from 0 (notpresent) to 4 (severe). Patients were then treated with Riluzole, aglutamate modulating agent, and HAM-D was followed weekly.

Methods. Thirteen patients between 18-65 years with anxiety symptomswere treated with the addition of riluzole to their existingpharmacotherapy. Hamilton Anxiety Inventory (HAM-A) scores were obtainedweekly.

Results: Thirteen study participants received Riluzole 50 mg twice aday. HAM-A scores for the group significantly improved over time(F_(1,10.8)=9.12, p=012; F_(1,11.2)=7.9, p=0.017, respectively).Riluzole was well tolerated with no serious adverse effects noted. FIG.5 shows pre- and post-treatment HAM-A scores for each study subject.Subjects P3, P5, P6, P7, P11, P12 with >/=35% reduction in HAM-A scorespost study treatment with Riluzole. FIG. 6 shows mean pre- andpost-treatment HAM-A scores for each study subject. Thirteen studyparticipants received Riluzole 50 mg twice a day. HAM-A scores for thegroup significantly improved over time (F_(1,10.8)=9.12, p=0.012;F_(1,11.2)=7.9, p=0.017, respectively). Mean Pre-TreatmentHAM-A=18.2+/−6.2 and Mean Post-Treatment HAM-A=12.8+/−7.2.

Conclusions: Riluzole appears to have significant anxiolytic properties.Riluzole addition appears of practical clinical benefit in patients withanxiety symptoms.

Summary

Taken together these findings demonstrate the usefulness of Riluzoleand/or glutamate modulating agents as anxiolytic agents in the treatmentof anxiety.

Trichotillomania

Case Report: Mrs. Z is a woman with long history of Trichotillomaniathat failed to respond to prior treatment with serotonin reuptakeinhibitor medications. She was being treated with Lexapro 30 mg andfailed to demonstrate a treatment response. Treatment with riluzole wasinitiated at 50 mg twice a day and titrated to 100 mg twice a day. Mrs.Z demonstrated a marked reduction in Trichotillomania symptoms asevidence by clinically significant reductions in Massachusetts GeneralHospital (MGH) Hairpulling Scale and Psychiatric InstituteTrichotillomania Scale (PITS). FIG. 7 shows a 74% Reduction in PITSscore after 6 weeks of treatment with Riluzole addition. FIG. 8 showspre- and post-riluzole treatment Massachusetts General Hospital (MGH)Hairpulling Scale score. There was a >35% Reduction in MGH Pulling ScaleScore after 12 weeks of treatment with Riluzole. Mrs. Z experienced acessation of Trichotollomania symptoms.

Summary

This case report demonstrate the usefulness of Riluzole and/or glutamatemodulating agents in the treatment of Trichotillomania.

EXAMPLE 3 Beneficial Effects of the Antiglutamatergic Agent Riluzole ina Patient Diagnosed with Trichotillomania

Trichotillomania (TTM) is an impulse-control disorder characterized bycompulsive hair-pulling. While the incidence of hair-pulling is quitehigh in some populations, full criteria for TTM are met by less than 1%of the population (Christensen et al., J. Clin. Psychiatry 52(10):415-7, 1991; King et al., J. Am. Acad. Child Adolesc. Psychiatry 38(12):1470-1, 1995; Walsh and McDougle, Expert Opin. Pharmacother. 6(6):975-84, 2005). Severe cases can lead to bald patches and markedsocial disability. Although TTM is categorized as an impulse-controldisorder, some clinicians conceptualize TTM as being part of a spectrumof disorders characterized by compulsive behavior, includingobsessive-compulsive disorder (OCD) and Tourette's syndrome. Thehypothesis that TTM and OCD are etiologically related is largely basedupon phenomenological similarity, high levels of comorbidity, and anincreased prevalence of OCD in first-degree relatives of TTM probands.While the proposition that OCD and TTM are related disorders remainscontroversial, it has motivated trials of pharmacological strategiesknown to be effective in OCD in patients with TTM. SSRI treatment of TTMhas shown inconsistent results: two double-blind placebo-controlledstudies of fluoxetine have failed to show any consistent benefit(Streinchenwein et al., Am. J. Psychiatry 152: 1192-1196, 1995;Christenson et al., Am. J. Psychiatry 148:1566-1571, 1991; Stanley etal., J. Clin. Psychiatry 52:282, 1991; Stanley et al., J. Clin.Psychopharmacol. 17 (4):278-83, 1997; reviewed in Walsh and McDougle,Expert Opin. Pharmacother. 6 (6):975-84, 2005); while clomipramine, atricyclic antidepressant with strong serotonin reuptake inhibitoryactivity, has shown benefit in TTM in a few clinical studies, though insome studies most patients appear to relapse after weeks or months ofcontinued treatment (e.g. Swedo et al., N. Engl. J. Med. 321(8):497-501, 1989; Swedo et al., N. Engl. J. Med. 329 (2):141-2, 1993;reviewed in Walsh and McDougle, Expert Opin. Pharmacother. 6 (6):975-84,2005). Augmentation of SSRI treatment with atypical antipsychotics,which is effective in some cases of SSRI-resistant OCD, has shown asignificant decrease in hair-pulling in some case reports and smallopen-label series (reviewed in Walsh and McDougle, Expert Opin.Pharmacother. 6 (6):975-84, 2005).

Preclinical and clinical observations suggest that dysregulatedglutamate activity may contribute to the pathophysiology OCD, and wehave observed benefit from drugs that modulate glutamatergicneurotransmission in preliminary studies (Pittenger et al., The Journalof the American Society for Experimental NeuroTherapeutics 3:69-81,2006). In particular, we found the antiglutamatergic drug riluzole(Rilutek, Aventis Pharmaceuticals), which is thought to reduce synapticglutamate, to be of benefit to patients with refractory OCD in aninitial open-label trial (Coric et al., Psychopharmacology, 167:219-220,2003; Coric et al, Biol. Psychiatry, 58:424-428, 2005). Here, wedescribe the successful use of riluzole in a patient with severe,chronic TTM.

Ms. B is a 53 year-old woman with a history of TTM and recurrent majordepression dating to adolescence. Previous adequate treatment trialswithout lasting effects included: cognitive behavioral therapy withexperienced clinicians, SSRIs (fluoxetine, fluvoxamine, citalopram,escitalopram) and other antidepressants (bupropion, clomipramine,venlafaxine). The longest period of abstinence for hair-pulling was athree-week period in the late 1980s during an early SSRI trial, butsymptoms returned shortly thereafter. At the time of presentation to ourclinic, Ms. B was taking escitalopram 30 mg daily without benefit to herhair-pulling or depressive symptoms, and she was able to go at most twodays without pulling.

The location of hair-pulling was mainly focused on the scalp, and shewore a hairpiece to cover her resultant frontal alopecia. Ms. Bcharacterized her distress from hair-pulling as moderate to severe.Hair-pulling at presentation was severe, as quantified by a PsychiatricInstitute Trichotillomania Scale (PITS) score of 23 and a MassachusettsGeneral Hospital (MGH) Hairpulling Scale score of 17 (see FIG. 9). Shealso reported depressed mood, helplessness, hopelessness, decreasedconcentration, decreased interest in activities, low energy, insomnia,and feelings of extreme guilt and shame. Her Hamilton Depression Index(HAM-D) at presentation was 26.

After obtaining informed consent for off-label use, we initiatedclinical treatment with riluzole at 50 mg twice a day. She experiencedan initial decline in hair-pulling but then experienced a resurgence insymptoms. Over the course of three months, her riluzole was titratedupwards to 150 mg and then 200 mg daily to target her residual TTM anddepressive symptoms. Depression improved rapidly, her HAM-D declined to7 by week 16 (see FIG. 9). With up-titration of riluzole, her urges topull vanished entirely, with a corresponding fall in her TTM ratings(see FIG. 9).

At recent follow-up (72 weeks after initiating riluzole treatment) Ms. Bhad continued on a stable dose of 100 mg twice a day of Riluzole andreported that urges to pull her hair continued to be minimal and readilyignored. Additionally, her improvement in mood persisted. Ms. B'sdecline in hair-pulling behaviors was also readily apparent bysignificant hair regrowth and continued reduction in TTM and depressivesymptom rating scales (see FIG. 9). Her longtime outpatient clinicianreported that Ms. B had previously been unable to maintain such anextended period free of significant hair-pulling, and found her to bemore socially proactive and assertive, insightful, resilient to externalstressors than at any time in the previous twenty years.

This case illustrates the potential utility of antiglutamatergic agentsin the treatment of refractory trichotillomania. This mirrors theapparent utility previously reported in small studies and case series inOCD (Coric et al., Psychopharmacology, 167:219-220, 2003; Coric et al,Biol. Psychiatry, 58:424-428, 2005), compulsive skin picking (Sasso etal., J. Clin. Psychopharmacolo., in press), and compulsiveself-injurious behavior (Pittenger et al., J. Clin. Psychiatry. 66(11):1492-3, 2005). In addition, the improvement in hertreatment-refractory depression adds to the growing literature on theutility of antiglutamatergic agents in the treatment of depression (e.g.Zarate et al., Am. J. Psych. 161:171-4, 2004; Zarate et al., Biol.Psych. 57:430-432, 2005; Sanacora et al., Ann. N.Y. Acad. Sci.1003:292-308, 2003; Sanacora et al., Am. J. Psychiatry. 161 (11):2132,2004). While the dramatic effect on her previously intractable TTM, inthe context of previous studies suggesting a role for riluzole in thetreatment of compulsive behavior syndromes, argues in favor of a directeffect of this glutamate modulating agent on her compulsivehair-pulling, it remains possible that the improvement of her TTM wassecondary to the marked improvement in her depression (thoughhistorically in this patient TTM had persisted even during periods ofimproved mood). Although generalizations made from single caseobservations are inherently limited, our observations in this patientsuggest that riluzole and other glutamate modulating agents meritfurther study in the treatment of refractory TTM.

EXAMPLE 4 Beneficial Effects of the Glutamate Modulating Agent Riluzoleon Disordered Eating and Pathological Skin Picking Behaviors Case Report

Ms. B was a 52-year-old woman with a long history of disordered eatingbehaviors, pathological skin picking, obsessions, compulsions,depression, and a prior diagnosis of Attention-Deficit/HyperactivityDisorder (ADHD). Diagnoses of OCD, Major Depressive Disorder (MDD), andAnorexia Nervosa were confirmed using the Structured Clinical Interviewfor DSM-IV Axis I Disorders-Clinician Version. Hasler et al., PsychiatryRes. 135 (2):121-32, 2005. Her family history was significant foranorexia in her mother, bipolar disorder in her maternal grandmother,and alcoholism in her brother, father, and paternal grandfather.

Ms. B's disordered eating behaviors began in adolescence and had beenpresent throughout adulthood. She alternated between periods of severerestricting, leading to multiple hospitalizations for failure to thrive,and periods of binging and purging. In the several-month period prior toadmission, Ms. B would eat one small meal a day and purge “once on agood day, four times on a bad day.” Ms. B also described longstandingskin picking behavior that was so severe that it led to recurrent facialinfections requiring the care of a dermatologist and occasionalantibiotic therapy. Any perceived flaw on her face would trigger theurge to scratch or squeeze the lesion, and she frequently used tweezersor pins for this purpose. She avoided social situations due to “shame”from the appearance of her excoriated facial skin. At the time of theinitial interview, Ms. B had multiple lesions at different stages ofhealing over her face. Ms. B's OCD symptoms included severe hoarding,collecting, and organizing behaviors as well as obsessions surroundinghygiene and compulsive cleaning.

Ms. B had previously had trials of several antidepressants (selectiveserotonin reuptake inhibitors [SSRIs], paroxetine, fluoxetine,citalopram, nefazodone, and escitalopram; the serotonin/norepinephrinereuptake inhibitor duloxetine, and the tricyclic antidepressantclomipramine) alone or in combination with mood stabilizers (lithium andvalproic acid) and antipsychotics (risperidone, ziprasidone, andaripiprazole). At the time of hospitalization, she had been on a stableregimen of fluoxetine 40 mg twice daily andamphetamine/dextroamphetamine 20 mg twice daily for two months.

Ms. B was admitted to the Clinical Neuroscience Research Unit of theAbraham Ribicoff Research Facilities (New Haven, Conn.). After providinginformed consent for off-label medication use, riluzole 50 mg twicedaily was added to her fluoxetine. Given the lack of prominent ADHDsymptoms, amphetamine/dextroamphetamine was tapered and discontinuedover three weeks. Riluzole was increased to 100 mg twice daily justprior to discharge to maximize symptom relief. Ms. B tolerated theriluzole well, complaining only of mild fatigue that resolved after thefirst several days of therapy. Liver enzymes were monitored monthly andremained stable. Ms. B participated in daily group and individualtherapy, and a behavioral exposure and response prevention plan wasinstituted to target her obsessive ironing and cleaning behaviors. Nospecific behavioral interventions were directed at her eating or skinpicking behaviors.

Eating behaviors were monitored by the patient's self-report andobservations by treatment staff during meals. Weekly weights were notrecorded, at the patient's request, due to extreme anxiety surroundingthe notion of having her weight known. Ms. B's skin picking behaviorswere also monitored by treatment staff, and she retrospectively reportedthe severity of these behaviors on the Skin Picking Impact Scale (SPIS),a 10-item validated self-report instrument designed to measure thepsychosocial impact of repetitive skin picking. Keuthen et al.,Psychosomatics 42 (5):397-403, 2001. OCD and depressive symptoms werefollowed weekly with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS),the Hamilton Rating Scale for Anxiety (HAM-A), and the Hamilton RatingScale for Depression (HAM-D.

Ms. B's symptoms improved significantly over the course of four weeks ofriluzole augmentation. In regard to her disordered eating behavior, sheinitially struggled with menu selection, reported multiple false foodallergies, and had difficulty eating in public at regularly scheduledmeal times. By the end of her hospitalization, she described thefollowing improvements: “I eat and don't obsess about it for hours. I'mokay eating at a table. I eat four times a day. I don't even get urgesto vomit.” During the second week of treatment, she purged twice in oneday. Thereafter, she reported only a single urge to vomit, in weekthree, which she was able to suppress. Regarding her eating behavioroverall, Ms. B reported on discharge, “Now, I feel like a regularperson.”

Ms. B also noted significant improvement in her skin picking behaviors(see FIG. 10B). She stated that her urge to pick became less intense andthat she no longer had to use make-up to cover facial lesions.Clinically, her skin looked healthier, with no obvious excoriated areas.On discharge, she reported that the skin picking behavior “is stillthere, but it's better.” This subjective improvement was consistent withstaffs observations of attenuated skin picking behaviors, notedimprovements in her facial lesions during direct clinical examination,and comparison of admission/discharge photographs.

Ms. B's scores on the Y-BOCS, HAM-A, and HAM-D improved steadily overthe course of treatment (see FIG. 10A). Her obsessions and compulsivebehaviors decreased, and she was able to reduce the amount of time shespent cleaning, ironing, and organizing. On the day of discharge,regarding her OCD symptoms, she noted, “This is as close to normal asI've ever felt. I've never had so much peace in my head.” Ms. B wasdischarged on riluzole 100 mg twice daily and fluoxetine 40 mg twicedaily.

Discussion

These clinical observations suggest the efficacy of aglutamate-modulating agent in the treatment of disordered eating andpathological skin picking. Glutamate participates importantly in theregulation of feeding behavior. Burns and Ritter, Pharmacol. Biochem.Behav. 56 (1):145-9, 1997; Zeni et al., Pharmacol. Biochem. Behav. 65(1):67-74, 2000; Georgescu et al., J. Neurosci. 25 (11):2933-40, 2005.Substantial data implicates glutamate and GABA in hypothalamic controlof feeding through modulation of neuropeptide Y andpro-opiomelancortin-containing neurons. Duva et al., Neurosci. Res. 52(1):95-106, 2005; Kiss et al., Neuroreport 8 (17):3703-7, 1997; van denPol, Neuron 40 (6):1059-61, 2003. Clinical studies have previouslysuggested efficacy of glutamate antagonists in disordered eatingbehaviors. Mills et al., Qjm. 91 (7):493-503. 1998; McElroy et al., Am.J. Psychiatry 160 (2):255-61, 2003; DeBernardi et al., Prog.Neuropsychopharmacol. Biol. Psychiatry 29 (2):339-41, 2005. Thepreclinical and clinical evidence for the effects seen here onpathological skin picking (PSP) behavior is less plentiful. Arnold andcolleagues (CNS Drugs 15 (5):351-9, 2001) have reviewed the literaturefor pharmacological approaches to PSP management, which includes tworandomized controlled trials of fluoxetine (Simeon et al., J. Clin.Psychiatry 58 (8):341-7, 1997; Bloch et al., Psychosomatics 42(4):314-9, 2001) in addition to several case reports and series.

It is unclear how antiglutametergic agents such as riluzole may treatdisordered eating and PSP behavior. Glutamate-modulating agents may havea nonspecific benefit on compulsive behaviors in general. Riluzole maypharmacologically modulate the reward value of these compulsivebehaviors. It is known that glutamate can affect activity in themesolimbic dopaminergic system, which is critically involved in rewardprocessing and motivated behaviors. Olds and Milner, J. Comp. Physiol.Psychol. 47 (6):419-27, 1954. Taber and Fibiger demonstrated glutamateregulation of feeding-evoked dopamine release in the ventral tegmentalarea and nucleus accumbens in rats. Neuroscience 76 (4):1105-12, 1997.More recent animal studies have demonstrated the effects of glutamateantagonists on attenuating self-administration of nicotine (Paterson etal., Psychopharmacology (Berl). 167 (3):257-64, 2003) and heroin (Xi andStein, Psychopharmacology (Berl). 164 (2):144-50, 2002).

The phenomenological theme of irresistible urge and tension that isrelieved when a compulsive behavior is performed is common to OCD,purging behavior, PSP, and drug-seeking behavior. This suggests theinvolvement of dysregulated reward pathways. Modulation of themesolimbic dopaminergic reward pathways by antiglutamatergic agents is aparsimonious explanation for riluzole's efficacy in all three domains ofsymptoms afflicting the patient described here.

Limitations of this study include those inherent to a single case reportand the retrospective collection of the SPIS ratings. In addition, it isimpossible to know whether the effects observed are attributable to theriluzole or to the beneficial effects of being in a structuredhospitalized environment away from the stressors of home or to thebehavioral interventions described above. However, the data presentedhere not only offer further support for the efficacy of riluzole intreatment-refractory OCD and depression, but supply preliminary evidencefor the efficacy of antiglutamatergic agents in disordered eating andpathological skin picking behavior. These findings provide grounds forfurther exploration of these potential therapeutic avenues and raise newquestions about glutamate's role in the neural circuitry underlyingvaried psychiatric symptomatology.

EXAMPLE 5 N-Acetylcysteine Augmentation in Serotonin Reuptake InhibitorRefractory Obsessive Compulsive Disorder

Ms. A was a 58 year-old woman with a history of childhood onset OCD whopresented with severe OCD symptoms consisting of contamination fears,intrusive ego-dystonic thoughts, hoarding behaviors, excessive handwashing and repetitive rituals performing her laundry. Her OCDsignificantly interfered with her ability to complete basic tasks oflife (including basic housekeeping and maintaining a sanitary homeenvironment), establish and maintain interpersonal relationships, andwas accompanied by feelings of self-loathing and shame. She had beenhospitalized five previous times secondary to her OCD symptoms; her lasthospitalization was twelve years prior to the current admission. Shereported having a stable but partial response to fluvoxamine, which shehad been taking at a dose of 300 mg daily for the preceding twelveyears. Previous medication trials of fluoxetine, clomipramine andalprazolam had failed, as had previous attempts at behaviormodification. She also had a history of recurrent major depressivedisorder that had been in remission for over twelve years. Her familyhistory was notable for a mother with depression, a father with alcoholabuse, and an uncle who committed suicide. She was perimenopausal at thetime of presentation and had a history of hyperlipidemia and borderlinehypertension but was taking no medications besides fluvoxamine.

Mrs. A presented to our clinic seeking help for persistent and severeOCD symptoms. Diagnosis of OCD was confirmed using the StructuredClinical Interview for DSM-IV Axis I Disorders-Clinician Version. Firstet al., Structured clinical interview for DSM-IV Axis I Disorders(SCID-I Clinician Version), American Psychiatric Press, Inc.,Washington, D.C., 1997. After informed consent, Ms. A was admitted tothe Clinical Neuroscience Research Unit of the Abraham Ribicoff ResearchFacilities (New Haven, Conn.) and treated clinically with an off-labeluse of NAC augmentation of fluvoxamine. OCD symptoms were followed usingweekly Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) ratings.

NAC (United States Pharmacia grade and in capsule form) was initiated ata starting dose of 600 mg PO daily and titrated upward to a total dailydose of 3 grams per day over 6 weeks. NAC was continued at the dose of 3grams per day for an additional seven weeks. Fluvoxamine 300 mg wascontinued throughout the NAC treatment period. Ms. A remained on theinpatient unit throughout the treatment period and received supportivepsychotherapy. She did not participate in a formal or manual-drivencognitive behavioral treatment plan. In fact, she was resistant toimplementing behavioral interventions given the past failure of suchinterventions.

Laboratory studies performed prior to the initiation of NAC revealedonly hyperlipidemia; routine lab monitoring over the course of heradmission revealed no further abnormalities. Ms. A reported a fewepisodes of mild, brief right hand tingling and a single day ofxerostomia, but no further side effects were noted.

Over the course of treatment with NAC augmentation, Ms. A's sense ofcontamination gradually decreased such that she began to be much lessdisturbed by intrusive thoughts of being contaminated. Y-BOCS scoredramatically decreased with time (FIG. 11). She became better able toresist her compulsive washing rituals and was able to confront manyobsessional triggers better than she had in many years. She wasdischarged home at the end of the trial with significantly improvedsymptoms and her symptoms remained improved at her two month follow-upvisit (at the same dose of NAC and fluvoxamine).

Although caution is advisable in generalizing the findings of a singlecase, the response of this patient to NAC may be consistent with ahypothesized role for glutamatergic dysfunction as a contributing factorto OCD symptoms in patients who have not benefited from SRIs. However,the exact nature of the mechanism through which NAC might reduce OCDsymptoms cannot be inferred from this case. As noted above, there are atleast three general mechanisms through which NAC might work. Our primaryhypothesis is that the benefits associated with NAC in this patientreflect that ability to reduce synaptic glutamatergic activity, perhapsvia group II metabotropic glutamate receptors. If so, then group IImetabotropic glutamate receptor agonists or positive allostericmodulators should also be explored as treatments for SRI-refractory OCDsymptoms. The “glutamate release inhibition” hypothesis is consistentwith evidence of glutamatergic hyperactivity in OCD and the preliminaryreport of the efficacy of riluzole, a drug that reduces glutamaterelease and stimulates glutamate uptake. Coric et al., Biol. Psychiatry58:424-428, 2005. However, NAC also raises extrasynaptic glutamatelevels and raises glutathione levels, and downstream consequences ofthese effects might have contributed to the current findings as well.The use of NAC in treatment-resistant OCD warrants furtherinvestigation, and may be advantageous over other glutamate modulatingagents given its tolerability and low cost.

EXAMPLE 6 Open-Label Study of Ceftriaxone Augmentation inSSRI-Refractory Obsessive Compulsive Disorder

The primary objective of this study is to demonstrate the efficacy ofceftriaxone (Rocephin®) in the treatment of SSRI-refractory OCD. Thereduction of OCD symptoms after two weeks of ceftriaxone therapy aremeasured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).Ceftriaxone is an FDA approved antibiotic medication and indicated for:lower respiratory tract infections, acute bacterial otitis media, skinand skin structure infections, urinary tract infections, uncomplicatedgonorrhea, pelvic inflammatory disease, bacterial septicemia, bone/jointinfections, intra-abdominal infections, surgical prophylaxis, andmeningitis. Ceftriaxone was previously without psychiatric indications.

Glutamate Dysregulation in OCD: Preclinical and Clinical Studies

A number of convergent lines of evidence support the notion thatdysregulation of glutamate neurotransmission contributes to thepathophysiology of OCD. This perspective is independent of themonoaminergic hypotheses that underlie established treatments. There isreason to hope, therefore, that patients whose symptoms are relativelyuntouched by pharmacological therapies aimed at the monoaminergicsystems may find relief in novel therapies aimed at normalizingglutamatergic neurotransmission.

Preclinical Evidence Suggesting Increased Glutamate Activity WorsensOCD-Like Behaviors

A few rodent models of OCD and OCD-spectrum disorders have beendeveloped. Joel, Prog Neuropsychopharmacol Biol Psychiatry, in press,2006. In some cases, involvement of molecules or brain regionshypothesized to be involved in OCD, or response to SSRI medication,lends specific rodent models of OCD a degree of face validity. Currentmodels are largely characterized by observable repetitive behaviors. Inone such model, transgenic mice express a neuropotentiating subunit ofthe cholera toxin in dopamine D1 receptor-expressing limbic corticalcells. This is presumed to increase their firing rate in a way that mayresemble the hyperactive limbic cortical areas seen in functionalimaging of OCD patients; indeed, these transgenic mice are described asengaging in perseverative behaviors that mimic some aspects of OCD andTourette's syndrome. MK-801, a non-competitive use-dependent antagonistof the NMDA glutamate receptor that indirectly increases presynapticglutamate release (Moghaddam et al., J. Neurosci. 17:2921-7, 1997), hasbeen shown to worsen these perseverative behaviors. Interestingly, NBQX,an antagonist of AMPA-type glutamate receptors, does not affect baselineOCD-like behaviors in these mice and does not attenuate the worsening ofOCD-like behaviors induced by MK-801. While numerous caveats must attendany interpretation of results from a methodologically limited animalmodel of OCD, the exacerbation of OCD-like behaviors by glutamatergicagents in this study supports an important role for increasedglutamatergic tone in the pathogenesis of obsessive-compulsive disorder,and with implications for its treatment.

Magnetic Resonance Spectroscopy (MRS) Measurements of GlutamateDysfunction in OCD

Magnetic resonance spectroscopy allows measurement of the concentrationof certain small molecules in the brain and other tissues. It has cometo be widely used in neurology as a tool to assess the health andcellular composition of different regions of the normal or diseasedbrain. The more recent development of methods to measure amino acidneurotransmitters in the brain has allowed levels of glutamatergiccompounds and GABA to be investigated in neuropsychiatric disorders.Recent MRS findings implicate dysregulation of glutamateneurotransmission in corticostriatothalamocortical (CSTC) circuits inOCD. Rosenberg and colleagues have reported abnormal Glx measurements inseveral brain regions in OCD. Int'l J. Neuropsychopharmacol. 4(2):179-90, 2001. Glx is increased in the striatum of patients with OCD,consistent with the known metabolic hyperactivity of the CSTC circuitry.Interestingly, this elevation in Glx has been shown to normalize in OCDsubjects who respond to treatment with SRI medications. In contrast,Rosenberg et al. found decreased Glx levels in the anterior cingulatedin subjects with OCD. As these authors point out, the combined findingof reduced anterior cingulate Glx concentrations and increased caudateGlx parallels prior studies demonstrating an inverse relationshipbetween anterior cingulate and basal ganglia volume in patients withOCD. The specific glutamatergic dysfunction in OCD remains to beelucidated and may vary between brain regions.

Elevated CSF Glutamate in OCD

The most direct evidence for excessive glutamatergic activity in OCDderives from a recent study examining cerebrospinal fluid (CSF) frompatients with OCD. Chakrabarty et al. examined the CSF of 21 drug-naïveOCD patients and 18 control subjects, and found CSF glutamate levels tobe significantly elevated in those subjects with OCD. Neuropsychopharm.,in press, 2006. This study requires replication with a larger number ofpatients, but it supports the MRS data in suggesting glutamatergicdysfunction as an important component of the pathophysiology of OCD.

Increased Cortical Excitability in OCD

Either increased glutamatergic tone or reduced GABA activity in thecortex may alter the excitatory-inhibitory balance in the cortex. Thisbalance can be probed with transcranial magnetic stimulation (TMS), bymeasuring the motor response to a threshold cortical stimulation andother parameters. Using this methodology, Greenberg and colleaguesrecently demonstrated increased cortical excitability in OCD. Neurology54:142-87, 2000. Future TMS studies are warranted to follow-up on thispreliminary finding.

Genetics

OCD, like many psychiatric disorders, is complex and presumablypolygenic. While OCD clearly has a heavy genetic loading, no clearlyreplicated genetic loci have been convincingly demonstrated to becausally involved in its pathogenesis. Nevertheless, several genesinvolved in glutamatergic neurotransmission have been implicated insingle association studies. Delorme et al., Neuroreport 15:699-702,2004. These include a preliminary association with the NMDA glutamatereceptor subunit GRIN2B and a negative association with a particularallele of the GRIK2 kainate receptor gene. Such associations are verypreliminary; but if these or similar genetic associations withcomponents of the glutamate neurotransmission and regulatory systems aresubstantiated, they would bolster the evidence that dysregulatedglutamate is an important aspect of the etiology of OCD.

The Use of Glutamate Modulating Agents Has Beneficial Effects inObsessive-Compulsive Disorder

The availability of pharmaceutical agents that directly attenuateglutamatergic outflow via potent glutamate modulating agents has onlyrecently become available. Riluzole (Rilutek; Aventis pharmaceuticals)is an antiglutamatergic agent that is FDA-approved for neuroprotectionin amyotrophic lateral sclerosis. Without intending to be limited bytheory, among the proposed mechanisms of action of riluzole areinhibition of sodium currents in glutamatergic (and other) axonterminals, reducing neurotransmitter release; reduction of P/Q-typecalcium currents in the axon terminals, with a similar effect ontransmitter release; extension of the open time of certain potassiumchannels and increased astrocytic uptake of glutamate. Although it hassignificant effects on glutamatergic function, riluzole is not a purelyan antiglutamatergic agent. In vitro studies suggest that it alsomodulates release of acetylcholine and dopamine, potentiates receptorsfor GABA and glycine, and enhances expression of BDNF.

Riluzole therapy has been reported in several neuropsychiatric disordersin which excessive glutamatergic activity has been implicated. Casereports and open label studies have been reported in the treatment ofmajor depression (Coric et al, Biol. Psychiatry, 58:424-428, 2005;Sanacora et al, Am. J. Psychiatry, 161:2132, 2004; Zarate et al., Am. J.Psychiatry, 161:171-174, 2004), bipolar depression (Zarate et al., Biol.Psychiatry, 57:430-432, 2005) anxiety (Coric et al, Biol. Psychiatry,58:424-428, 2005), and OCD with major depression (Coric et al.,Psychopharmacology, 167:219-220, 2003; Coric et al, Biol. Psychiatry,58:424-428, 2005).

These promising early results with riluzole encourage trials of otherglutamate-modulating agents in OCD. An exciting new possibility israised by a recent study revealing unexpected glutamate modulatingproperties of beta-lactam antibiotics. Rothstein and colleagues testedover 1,000 drugs in an in vitro assay and found that multiplebeta-lactam compounds specifically upregulated the glial glutamateuptake transporter; tested beta-lactams proved to have neuroprotectiveeffects in a mouse model of amyotrophic lateral sclerosis, demonstratingthe physiological activity of the compounds. Rothstein et al., Nature,433:73-77, 2005. Because of the extensive tolerability data on suchcompounds, they represent an exciting and unexpected group of potentialantiglutamatergic agents for use in OCD and other neuropsychiatricdisorders. Rothstein and colleagues demonstrated that ceftriaxone(Rocephin) upregulated the glial glutamate transporter more so than manyother drugs. Also, their preclinical evidence suggests that beta-lactamantibiotics offer neuroprotection by selectively inducing transcriptionof the gene encoding the EAAT2 glutamate transporters, which are pumpsthat allow efficient recovery of released glutamate such that glutamatesignaling is rapidly silenced, and prevent glutamate neurotoxicity.Rothstein et al., Nature, 433:73-77, 2005; Brown, N. Engl. J. Med.,352:13, 2005. Ceftriaxone was shown to be neuroprotective when used inan animal model of Amyotrophic Lateral Sclerosis (ALS), ischemic injury,and motor neuron degeneration by increasing glutamate transport, asmeasured by L-[³H] glutamate uptake into cortical membrane. See FIG. 3dof Rothstein et al., Nature, 433:73-77, 2005. Based on these findings,the development of clinical trials of ceftriaxone in subjects with ALSis underway. Brown, N. Engl. J. Med., 352:13, 2005.

An Open-Label Study to Evaluate the Tolerability and Efficacy ofCeftriaxone (Rocephin) in the Treatment of Refractory OCD Overall StudyDesign

The efficacy of ceftriaxone treatment in SRI-refractoryobsessive-compulsive disorder (OCD) is studied. Patients who meet thediagnostic criteria for OCD as stated in The Diagnostic and StatisticalManual of Mental Disorders, 4th edition-Text Revised (DSM-IV-TR) andhave failed to respond to standard treatment with a serotonin reuptakeinhibitor (SRI) are eligible.

Fifteen OCD patients are enrolled either as outpatients or inpatientsdepending on their clinical condition for a 4-week medication trial.Inpatients are admitted to the Clinical Neuroscience Research unit forthe 4-week medication trial. The CNRU is a locked inpatient psychiatricunit devoted to clinical psychiatric research and is located on thethird floor of the Connecticut Mental Health Center. The unit cares forindividuals who are voluntarily admitted to try new treatments for theirillnesses. Individuals admitted to the unit suffer from a variety ofpsychiatric illnesses. The CNRU houses, at most, thirteen researchparticipants at any given time. Inpatient subjects are expected toremain inpatients for the entire four weeks of the study; however,patients routinely leave the unit three times a day for outside breaksand passes as warranted by their clinical condition. In an event that aninpatient subject decides to leave and wishes to continue the study asan outpatient, provisions are outlined to accommodate their preference.For example, as outpatient subjects, they are required to come in once aweek for their weekly psychometric assessments and other tests. In thepast studies, such accommodations have been granted even for out-of-townsubjects. Visitors are allowed during scheduled visitation hours only.The inpatient setting may be required for the more severely illpopulation of patients who participate in this study. Individuals withrefractory OCD who are willing to travel from other states for anopportunity to receive a novel treatment and inpatient care mayparticipate in the study. Locally recruited subjects who meet inclusioncriteria and desire an inpatient hospitalization are also be offered theopportunity for an inpatient admission if clinically indicated. Afterpatients have provided informed consent and are screened foreligibility, they are enrolled in the trial.

Baseline assessments and basic laboratory work-up are performed on Days1-3. Patients are continued on all their current medications unlesscontraindicated. On Day 4, all enrolled patients start the study trialwith ceftriaxone 2 gm once a day. The dose of the study drug remains thesame during the entire study. Experimental subjects receive weeklypsychometric assessments.

Study Schedule Screening and Initial Assessments (Day 1-3)

The screening evaluation includes an assessment of whether the patientqualifies based on inclusion/exclusion criteria (see below, SubjectPopulation). In addition, the following assessments or procedures arecompleted at Day 1 to determine the subject's eligibility:

All Subjects

-   Written informed consent (competency to provide consent is to be    judged by the investigator). Whenever indicated, the patient's    primary clinician, family and significant others will be involved in    the consent process.-   Demographic data; medical history; psychiatric history, including    documentation of clinical diagnosis; and current medication usage-   Confirmation of diagnosis with Structured Clinical Interview for    DSM-IV Axis I disorders (SCID-I)-   Physical and neurological examination, including measurement of    blood pressure, heart rate, weight and height-   Clinical laboratory tests including liver function tests,    hematology, clinical chemistry, thyroid function tests.-   Urine human chorionic gonadotrophin (HCG) pregnancy test (for all    women) 12-lead ECG.

Prior medication history

-   Baseline Y-BOCS-   Placement of PICC line

The Following Psychometric Assessments or Procedures are Conducted onDays 2-3

-   CGI Severity of Illness item-   Hamilton Rating Scale for Anxiety (HAM-A)-   Hamilton Rating Scale for Depression (HAM-D)-   Beck Depression Inventory (BDI)-   Screen for tic disorders using the relevant portions of the Schedule    for Tourette's Syndrome and-   Other Behavioral Syndromes for DSM-IV and the Yale Global Tic    Severity Scale (rated from 0=none to 5=always) used to measure    frequency of tics for those with tics.-   Dysfunctional Attitude Survey (DAS)-   Attributional Style Questionnaire (ASQ)-   Social Adjustment Scale (SAS)

Treatment Phase (Days 4-14)

-   Subjects receive Ceftriaxone 2gm thru a PICC (peripherally Inserted    Central Catheter) line, once-a-day and remain at this dose for the    four weeks of the study. Subjects will receive weekly psychometric    assessments.-   Routine serum chemistry, hematology are collected periodically as    clinically indicated.-   Stool is analyzed for Clostridium difficile if subject experiences    diarrhea for three consecutive days.

Outcome Measures

Assessments are performed as per the schedule of study procedures. Theoutcome measures include:

Primary Measure

The mean difference from baseline Y-BOCS score at end of treatment (week4).

Secondary Measures

-   The proportion of patients who achieve reductions of 35% or greater    from baseline Y-BOCS total score at weeks 1-12 or at withdrawal from    the study.-   The mean change in Clinical Global Impression score measured at the    end of each week between medication and placebo groups-   The mean change in Hamilton Depression and Anxiety measured at the    end of each week.-   The mean change in Beck Depression scale measured at the end of each    week.-   The change in Yale Global Tic Severity Scale (if tics are present).-   Other tolerability and safety measures will include the reporting of    adverse events, clinically significant changes in the results of    hematology and clinical chemistry tests (including liver function    tests, thyroid function tests, serum glucose and lipid    concentrations measured under fasting conditions), vital signs, and    electrocardiogram results.-   Subjects' symptomatology will be evaluated throughout the trial.    After an initial inquiry, the subject will be asked, “Has anything    bothered you since the last visit (or last assessment)?” Patients    also will be instructed to volunteer AE's noted any time during the    trial.-   The following criteria are used to define treatment response:-   35% or greater improvement on Y-BOCS from baseline and a final    Y-BOCS of 16 or less.-   a final CGI rating of “much improved” or “very much improved”-   Consensus of the treating clinician and two of the primary    investigators that the patient's condition was improved.

Study Medications

Ceftriaxone is obtained from the CMHC pharmacy. Trial medication isdosed at 2 gm and administered thru a PICC line, once a day, throughoutthe four week (28 day) treatment period.

All previously administered psychoactive medications, includingbenzodiazepine, anxiolytic, neuroleptic, antidepressant, and moodstabilizing medication, are continued throughout the study.

Concomitant Medications

Initiation of concomitant medication use during the trial is restrictedas stated below.

-   Antidepressant, anxiolytic, neuroleptic and mood-stabilizing    medication usage will be permitted only if it has been prescribed at    least one month prior to Day 1 of the trial. Patients taking    medication for sleep can continue to do so provided it is taken only    at bedtime for sleep.-   The use of potent cytochrome P450 inducers (including but not    limited to carbamazepine, phenobarbital, and phenytoin) and    inhibitors (including but not limited to ketoconazole, azole    antifungals, erythromycin, macrolide antibiotics, and protease    inhibitors) is not permitted within 14 days of baseline (Day 1) or    during the randomized treatment period. Women who enter the trial    with an intrauterine device in place, using oral contraceptives, or    using injectable or implantable hormonal agents designed to prevent    pregnancy may continue these treatments throughout the trial.

Use of other prescription and nonprescription medications must be agreedupon before each patient is enrolled. Acetaminophen (without caffeine)preparations are the only medications allowed for analgesia.

Subject Withdrawal

Patients may be withdrawn from the trial for any of the followingreasons:

-   lack of efficacy (requiring alternative treatment)-   adverse effects (including positive stool sampling for Clostridium    difficile)-   subject lost to follow-up (dropouts)-   protocol noncompliance (protocol violations or deviations)-   withdrawal of consent-   at the investigator's discretion

Any subject who withdraws during the trial and has clinicallysignificant or abnormal findings on any safety assessment will have afollow-up visit within 1 week and at appropriate intervals thereafteruntil the abnormality resolves. Where possible, patients are followed upfor 30 days after the last dose of trial drug is given.

Primary Analysis

Y-BOCS scores in SRI-refractory OCD subjects decrease as a result ofcompletion a 4-week course of Ceftriaxone treatment. All outcomes aresummarized descriptively and assessed for normality prior to analysisusing normal probability plots and Kolmogorov test statistics.Transformations or nonparametric analyses are performed as necessary.The primary outcome in this study is the Y-BOCS measured over time andis evaluated using linear mixed models where time (baseline, weeks 1-4)is included as a within-subject explanatory factor. The best fittingvariance-covariance structure is chosen based on information criteria.Appropriate post-hoc comparisons is performed to compare levels betweendifferent time points. Secondary outcomes are evaluated using similarmodels.

Secondary Analyses

HAM-D, HAM-A and CGI scores improve after Ceftriaxone augmentation.Paired t-tests or non-parametric equivalents are used for comparison ofpre- versus post-treatment changes in these secondary outcome measures.Treatment response rates are estimated by proportion of subjects meetingcriteria as defined in the Outcome Measures section. Exploratoryrepeated measures analyses with time as within-subject factor areperformed on all outcome measures.

Sample Size Calculation

In the above-described study examining the effects of riluzole intreatment-resistant OCD patients and using a similar protocol to the oneproposed here, the effect size in the comparisons of Y-BOCS betweenbaseline and week 4 was 0.86. Coric et al, Biol. Psychiatry, 58:424-428,2005. With a sample size of 15, based on a 2-tailed, paired t-test andalpha=0.05, there is an 80% statistical power to detect an effect sizeof 0.78. Thus, there is ample power to detect smaller effects than thosefound previously in a similar protocol.

Human Subjects Inclusion Criteria, Subjects with Primary Diagnosis ofOCD

-   1) Voluntary signed informed consent prior to the performance of any    study specific procedures-   2) Subjects with a DSM-IV diagnosis of OCD that has failed to fully    respond to at least 8 weeks of treatment with a Serotonin Reuptake    Inhibitor (failure to fully respond as defined by a Y-BOCS score of    greater than 16 despite SRI treatment)-   3) OCD symptoms at least of one year's duration and of least    moderate severity on the Clinical Global Impression Scale (CGI).-   4) Males or Females between ages 18-65 year old. For females only:    The subject must be non-pregnant, non-breast feeding and using an    effective form of birth control or the subject must be least one    year post-menopausal; or the subject a) has a negative urine    pregnancy test (Beta-HCG), and b) agrees to practice contraception    throughout the study.

Exclusion Criteria, Subjects with Primary Diagnosis of OCD

-   1) Diagnosis of a primary psychotic disorder.-   2) Active illicit substance abuse/dependence in the last one month-   3) Subjects who have had psychosurgery-   4) Recent (<1 month) change in psychotropic medications-   5) Presence of clinically significant somatic disease and/or medical    problem that requires frequent changes in medication.-   6) History of or current seizure disorder-   7) Evidence of Substance Use Disorder (DSM-IV) within past 1 months    or current illicit drug use.-   8) Known to be HIV positive.-   9) Subjects known to have a previous allergic reaction to    ceftriaxone or an anaphylactic reaction to penicillin.-   10) Women who are pregnant, breast feeding, or of childbearing    potential (not sterile nor using acceptable birth control).

Fifteen subjects with SRI-refractory OCD are recruited for the study.Eligible subjects are over 18 years old, of either gender, and meet theinclusion and be without any exclusion criteria as described above.

EXAMPLE 7 Tail Suspension Test

10 mice treated for 7 days with ceftriaxone and 10 mice treated withsaline for 10 days were studied using the tail suspension test forantidepressant properties. The tail suspension test is a commonly usedmodel to test antidepressant properties of novel drug compounds. Asshown in FIG. 12 (after 7 days; 1 injection/day; C57BL/6J males; 10animals/group; 16 weeks of age), there was nearly a 20% decrease in theimmobility time (this percent reduction in immobility is consistent withthe response observed with antidepressant medications) and a trend forincreased latency and decreased bouts of immobility in the micepretreated with ceftriaxone. Ceftriaxone is a beta-lactam antibioticdrug known to increase glutamate clearance through the alteredexpression and function of glutamate transporters. These resultsdemonstrate that ceftriaxone has antidepressant properties and would bean effective treatment for depressive disorders and other psychiatricdisorders involving altered glutamate function.

All patents, patent publications, and other published referencesmentioned herein are hereby incorporated by reference in theirentireties as if each had been individually and specificallyincorporated by reference herein.

While specific examples have been provided, the above description isillustrative and not restrictive. Any one or more of the features of thepreviously described embodiments can be combined in any manner with oneor more features of any other embodiments in the present invention.Furthermore, many variations of the invention will become apparent tothose skilled in the art upon review of the specification. The scope ofthe invention should, therefore, be determined by reference to theappended claims, along with their full scope of equivalents.

1-34. (canceled)
 35. A method for treating a mental disorder in apatient in need thereof, comprising administering to the patient aneffective amount of riluzole or its prodrug in a pharmaceutical dosageform in combination with at least one pharmaceutically acceptablecarrier, wherein the mental disorder is dementia.
 36. The methodaccording to claim 35, wherein the dementia is dementia is due toAlzheimer's disease, vascular dementia, dementia due to head trauma,dementia due to Parkinson's disease, dementia due to Huntington'sdisease, dementia due to Pick's disease, dementia due toCreutzfeldt-Jakob disease, dementia due to normal-pressurehydrocephalus, dementia due to traumatic brain injury, dementia due to abrain tumor, dementia due to anoxia, dementia due to an infectiousdisorder, dementia due to a vitamin deficiency, dementia due to animmune disorder, dementia due to a hepatic condition, dementia due to ametabolic condition, dementia due to multiple sclerosis,substance-induced persisting dementia, or dementia due to multipleetiologies.
 37. The method according to claim 35, wherein the dementiais due to Alzheimer's disease.
 38. The method according to claim 35,wherein the dementia is due to Alzheimer's disease with an early onset.39. The method according to claim 35, wherein the dementia is due toAlzheimer's disease with a late onset.
 40. The method according to claim37, wherein the Alzheimer's disease is uncomplicated.
 41. The methodaccording to claim 37, wherein the Alzheimer's disease is accompanied bydelirium, delusions, depressed mood, or a combination thereof.
 42. Themethod according to claim 37, wherein the Alzheimer's disease isaccompanied by brain atrophy.
 43. The method according to claim 37,wherein the Alzheimer's disease is accompanied by cerebrovasculardisease.